As both men and mice age, their immune systems lose their ability to function normally. Functions that can be measured without permanently affecting the mice will be emphasized. Whether a significant part of the decline with age is intrinsic in immunological stem cell lines is an important and controversial issue. The long-term functional abilities of stem cell lines can be tested by transplantation into stem cell depleted recipients. We are developing methods that test maximal long-term function and allow quantitative identification of donor stem cell lines. Such tests will be used to compare stem cell lines from old and young donors, and to study the surprisingly deleterious effect of transplantation; they are the first tests of long-term immunological stem cell functions to be developed. Using these tests a decline with age in hybrid resistance, and a quantitative measure of immune responses against marrow grafts were recently discovered; both will be further investigated. It is possible that the decline with age in immune response or in hybrid resistance allows growth of tumors that otherwise would have been suppressed, and this possibility will be investigated. We will also determine whether hybrid resistance to tumor cell growth declines with recipient age. Treatments will be tested that may retard or reverse immunological declines with age. These include irradiation followed by marrow and thymus transplantation, food restriction, hypophysectomy, and parabiosis. Detailed measurements of immunological changes will be supplemented by measuring other physiological changes in the same individuals, and determining whether other systems show the same aging pattern as the immune system. The effects of treatments on longevity will be determined.